Although progress has been made, we still lack a truly efficient chemotherapy against human immunodeficiency virus (HIV) infection and progression towards AIDS. HIV requires T cell activation and blastogenesis for efficient replication in vitro, thus agents which induce T cell activation and blastogenesis enhance HIV replication. There is evidence to suggest that T cell activation is also required for HIV replication in vivo. Consequently we have attempted to develop a strategy to inhibit HIV replication and progression to AIDS based on these observations. Dehydroepiandrosterone (DHEA), a major adrenal secretory product in men and women, is a potent inhibitor of mammalian glucose-6- phosphate dehydrogenase (G6PDH). DHEA has previously been found to suppress Epstein-Barr virus (EBV)-induced morphologic transformation and stimulation of DNA synthesis in human peripheral blood lymphocytes (PBLs) (Henderson et al., Carcinogenesis 2:683, 1981). 16 alpha-Br-epiandrosterone, a DHEA analog, is about 60 times more potent than DHEA as an inhibitor of G6PDH, and is much more effective as an inhibitor of EBV-induced transformation. The ability of ribonucleosides and deoxyribonucleosides to 1 reverse the anti-proliferative and anti-differentiating effects of DHEA strongly suggests that inhibition of nucleic acid synthesis is a primary target for these biological effects of DHEA and DHEA analogs. In preliminary experiments we have found that novel synthetic analogs of DHEA, 16 alpha-fluoro-5-androsten-17-one (8354) and 3 beta-hydroxy-16 alpha-fluoro-5 alpha-androstan-17-one (hydroxy 8356) inhibit HIV replication in PHA-treated PBLs. Inhibition of HIV replication was not due to cell toxicity of these compounds. Since DHEA and its analogs are relatively nontoxic, they represent a novel class of compounds with potential for therapy of HIV-infected individuals. Here we propose 1) to directly test this hypothesis by examining the ability of DHEA and synthetic analogs of DHEA to inhibit HIV replication in control and phytohemagglutin (PHA)-stimulated PBLs and continuously proliferating T cell lines; 2) test the ability of DHEA and synthetic analogs to act synergistically with 3'azido-2',3'- dideoxythymidine (AZT) in inhibiting HIV replication. DHEA or its synthetic analogs has the potential of being an efficient adjunct therapy with conventional antiviral compounds in treating HIV infection.